Alternative titles; symbols
HGNC Approved Gene Symbol: CD59
Cytogenetic location: 11p13 Genomic coordinates (GRCh38): 11:33,703,010-33,736,479 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p13 | Hemolytic anemia, CD59-mediated, with or without immune-mediated polyneuropathy | 612300 | Autosomal recessive | 3 |
Okada et al. (1989) described a novel membrane inhibitor of the membrane attack complexes (MACs). A 20-kD protein, its function is the same as that of HRF (homologous restriction factor), which has a molecular mass of 65 kD. Therefore, they termed the new protein HRF20. HRF20 was also found to be identical to membrane attack complex inhibitory factor (MACIF) and CD59 (Davies et al., 1989); the sequences of cDNA encoding the 3 were essentially identical. By means of flow cytometric analysis, HRF20 was found to be expressed on most leukocytes and erythrocytes, indicating that it may have a role in preventing complement attack in the circulation.
By searching for genes in a region of chromosome 11 associated with WAGR syndrome (194072), Gawin et al. (1999) identified and cloned CD59, which they designated clone 44686. Northern blot analysis detected variable expression of a 6-kb transcript in all human tissues examined.
The CD59 antigen recognized by monoclonal antibody MEM-43 is an 18- to 25-kD glycoprotein expressed on all human peripheral blood leukocytes, erythrocytes, and several human cell lines. A close relationship to Ly6 of the mouse has been demonstrated. Antigens encoded by both Ly6 and CD59 genes are important to T-cell and NK-cell function. CD59 is also known as protectin. Its function is to restrict lysis of human erythrocytes and leukocytes by homologous complement. By directly incorporating protectin into membranes of heterologous cells, Meri et al. (1990) found that protectin does not prevent perforin-mediated killing (see 170280), whereas complement killing is effectively restricted. Thus, cell-mediated killing is unaffected by protectin. Meri et al. (1990) described the functional characteristics of protectin. Much attention has been focused on the Ly6 proteins because they may be involved in lymphocyte activation, and expression of some of them occurs at critical times in the differentiation of lymphocytes.
Walsh et al. (1992) reviewed information on CD59, which they characterized as a multifunctional molecule with a role particularly in inhibition of formation of membrane attack complex. They raised the possibility that Ly6 is not a homolog and that the true MAC-inhibiting murine homolog of CD59 had yet to be found.
Rother et al. (1994) demonstrated that retroviral transduction with a recombinant transmembrane form of CD59 of mouse L cells deficient in GPI anchoring resulted in surface expression of the CD59 protein and resistance of these cells to human complement-mediated membrane damage. Furthermore, a GPI anchoring-deficient complement-sensitive B-cell line derived from a PNH patient was successfully transduced with the particular form of recombinant CD59, resulting in surface expression of the protein. These cells were protected against classic complement-mediated membrane damage by human serum. The findings suggested that retroviral gene therapy with this molecule could provide a treatment for patients with paroxysmal nocturnal hemoglobinuria (PNH; 300818).
Mao et al. (1996) suggested that the RIGE gene (601384) is the closest human homolog of the murine Ly6 gene family.
Activated terminal complement proteins C5b (120900) to C9 (120940) form the MAC pore. Insertion of the MAC into endothelial cell membranes causes the release of growth factors that stimulate tissue growth and proliferation. The complement regulatory membrane protein CD59 restricts MAC formation. Because increased cell proliferation characterizes the major chronic vascular complications of diabetes, and because increased glucose levels in diabetes cause protein glycation and impairment of protein function, Acosta et al. (2000) investigated whether glycation could inhibit CD59. Glycation-inactivation of CD59 would cause increased MAC deposition and MAC-stimulated cell proliferation. They reported that (1) human CD59 is glycated in vivo; (2) glycated human CD59 loses its MAC-inhibitory function; and (3) inactivation of CD59 increases MAC-induced growth factor release from endothelial cells. They demonstrated by site-directed mutagenesis that residues lys41 and his44 form a preferential glycation motif in human CD59. The presence of this glycation motif in human CD59, but not in CD59 of other species, may help explain the distinct propensity of humans to develop vascular proliferative complications of diabetes.
The placenta is an immunologically privileged site. Using DNA microarrays to compare gene expression patterns, Sood et al. (2006) found that 3 regulators of complement, CD55 (125240), CD59, and membrane cofactor protein (MCP; 120920), are expressed at higher levels in normal placental villus sections compared with other normal human tissues. Within the placenta, CD55 and CD59 are expressed at greatest levels in amnion, followed by chorion and villus sections, whereas MCP is expressed at higher levels only in villus sections. These inhibitors of complement are expressed on syncytiotrophoblasts, the specialized placental cells lining the villi that are in direct contact with maternal blood. The amnion compared with chorion is remarkably nonimmunogenic, and the immune properties of the amnion are intriguing because it is not in direct contact with maternal cells. Sood et al. (2006) suggested that the amnion may secrete the complement inhibitors themselves or in the form of protected exosomes into the amniotic fluid or the neighboring maternofetal junction.
Morais da Silva et al. (2002) showed that the newt ortholog of CD59, Prod1, is involved in determining the proximodistal identity of blastemal cells during limb regeneration. Human CD59 shares 23% amino acid identity with newt Prod1 and 34% identity with mouse Cd59. All 3 proteins contain a conserved CD59/Ly6 family motif (CCxxxxCN), and 8 of the 10 cysteines conserved in mouse and human CD59 are found in newt Prod1. Like CD59, Prod1 attaches to the cell surface through a glycosylphosphatidylinositol (GPI) anchor that is cleaved by phosphatidylinositol-specific phospholipase C (see 604114).
Kumar et al. (2007) found that in the adult salamander, limb regeneration is dependent upon the surface protein Prod1 as a critical determinant of proximodistal identity. The anterior gradient protein family member newt AG, whose human homolog is AG2 (606358), is a secreted ligand for Prod1 and a growth factor for cultured newt blastemal cells. Newt AG is sequentially expressed after amputation in the regenerating nerve and the wound epidermis--the key tissues of the stem cell niche--and its expression in both locations is abrogated by denervation. The local expression of newt AG after electroporation is sufficient to rescue a denervated blastema and regenerate the distal structures. Kumar et al. (2007) concluded that their analysis brought together the positional identity of the blastema and the classical nerve dependence of limb regeneration.
Petranka et al. (1992) demonstrated that the CD59 gene contains 4 exons spanning 20 kb. The untranslated first exon is preceded by a G+C-rich promoter region that lacks a consensus TATA or CAAT motif. The second exon encodes the hydrophobic leader sequence of the protein, and the third exon encodes the N-terminal portion of the mature protein. The fourth exon encodes the remainder of the mature protein, including the hydrophobic sequence necessary for GPI anchor attachment. They found that the structure of the CD59 gene is similar to that encoding Ly6. Similarity in gene structure suggests that the 2 proteins belong to a superfamily of proteins that may also include the urokinase plasminogen activator receptor (173391).
Tone et al. (1992) reported that the CD59 gene is more than 27 kb long and comprises one 5-prime untranslated exon and 3 coding exons. Northern blot analysis using 6 different probes located in the 3-prime region of the gene showed that more than 4 different CD59 mRNA molecules are generated by alternative polyadenylation. Three of these polyadenylation sites were predicted from previously published cDNA sequences.
Forsberg et al. (1989) used indirect immunofluorescence and immunoblotting with MEM-43 antibody to demonstrate expression of CD59 in Chinese hamster-human cell hybrids. CD59 was found to segregate with hybrids containing part of the short arm of human chromosome 11 but not with hybrids containing the long arm. They specifically assigned the gene to 11p14-p13. Heckl-Ostreicher et al. (1993) used chromosomal in situ hybridization and pulsed field gel electrophoresis to map the CD59 gene to 11p13, distal to the breakpoint of acute T-cell leukemia (LMO2; 180385) and proximal to the Wilms tumor gene (WT1; 607102). Ly6 is on mouse chromosome 15 (LeClair et al., 1987). Indeed, the Ly6 multigene family is clustered in a region closely linked to the Sis (190040) and Myc (190080) protooncogenes (Huppi et al., 1988). Kamiura et al. (1992) used the combined techniques of field-inversion gel electrophoresis (FIGE), phage and cosmid genomic library screening, and 2-dimensional DNA electrophoresis to construct a physical map of the entire Ly6 complex. The map spanned approximately 1,600 kb. Bickmore et al. (1993) assigned the CD59 gene to 11p13 by study of somatic cell hybrids and by pulsed field gel electrophoresis, as well as by the fact that the gene is often deleted in WAGR individuals. This region of chromosome 11 shows homology of synteny with mouse chromosome 2. This suggested that CD59 is not a homolog of the mouse Ly-6 gene on mouse chromosome 15, but rather is a related gene.
Holt et al. (2000) cloned the mouse CD59 homolog and mapped the gene by radiation hybrid analysis to chromosome 2 in a region showing conserved synteny with human 11p13.
Motoyama et al. (1992) identified a single-nucleotide deletion (107271.0001) in the CD59 gene in a patient with CD59-mediated hemolytic anemia (HACD59; 612300) manifest as paroxysmal nocturnal hemoglobinuria.
In 5 patients from 4 unrelated families of North African Jewish descent with CD59-mediated hemolytic anemia and immune-mediated polyneuropathy (612300), Nevo et al. (2013) identified a homozygous mutation in the CD59 gene (C89Y; 107271.0002). The mutation was initially found by whole-exome sequencing in 2 affected sibs, segregated with the disorder in all families, and was not found in the dbSNP or the Exome Variant Server database. Haplotype analysis indicated a founder effect. The patients presented in infancy with a relapsing-remitting polyneuropathy, often exacerbated by infection, and characterized by hypotonia, limb muscle weakness, and hyporeflexia. The patients also showed chronic hemolytic anemia. Immunosuppressive treatment resulted in some clinical improvement. Red blood cells derived from the patients showed lack of CD59 expression, and sural nerve biopsy of 1 patient showed no CD59 expression. Western blot analysis detected reduced amounts of the protein, suggesting that it is synthesized but fails to reach cell membranes. Because C89Y disrupts a disulfide bond, the tertiary structure of the mutant protein may be affected. Nevo et al. (2013) suggested that improper activation of the complement system due to lack of CD59 expression may cause damage to red cell membranes and result in myelin and axonal damage.
To examine the role of CD59 in protecting host tissues in health and disease, Holt et al. (2001) generated Cd59-deficient (Cd59 -/-) mice by gene targeting in embryonic stem cells. Despite the complete absence of Cd59, mice were healthy and fertile. Red cells in vitro displayed increased susceptibility to complement and were positive in an acidified-serum lysis test. Despite this, Cd59 -/- mice were not anemic but had elevated reticulocyte counts, indicating accelerated erythrocyte turnover. Fresh plasma and urine from these mice contained increased amounts of hemoglobin when compared with littermate controls, providing further evidence for spontaneous intravascular hemolysis. Intravascular hemolysis was increased following administration of cobra venom factor to trigger complement activation.
In a 23-year-old Japanese male with complete deficiency of CD59 (HACD59; 612300), Motoyama et al. (1992) identified single-nucleotide deletions in codon 16 (GCC to GC) and codon 96 (GCA to CA). The homozygous deletion in codon 16 resulted in a frameshift and introduced a stop codon at position 54. The parents, who were cousins, were heterozygous for the mutation. One sister was also heterozygous; a brother was homozygous normal. Presumably it was the deletion in codon 16 that was responsible for the effects on the protein resulting in CD59 deficiency. The patient presented with paroxysmal nocturnal hemoglobinuria with onset in adolescence. He had no involvement of the peripheral nervous system at age 22 years (Nevo et al., 2013).
In 5 patients from 4 unrelated families of North African Jewish descent with CD59-mediated hemolytic anemia and immune-mediated polyneuropathy (HACD59; 612300), Nevo et al. (2013) identified a homozygous c.266G-A transition in exon 3 of the CD59 gene, resulting in a cys89-to-tyr (C89Y) substitution at a highly conserved residue that participates in the formation of a disulfide bond. The mutation was found by whole-exome sequencing in 2 affected sibs, segregated with the disorder in all families, and was not found in the dbSNP or the Exome Variant Server database. Haplotype analysis indicated a founder effect, and the mutation was found in heterozygous state in 3 of 197 ethnically matched individuals (carrier rate of 1 in 66 in this community). Red blood cells derived from the patients showed lack of CD59 expression, and sural nerve biopsy of 1 patient showed no CD59 expression. Western blot analysis detected reduced amounts of the protein, suggesting that it is synthesized but fails to reach cell membranes. Because C89Y disrupts a disulfide bond, the tertiary structure of the mutant protein may be affected. Nevo et al. (2013) suggested that improper activation of the complement system due to lack of CD59 expression may cause damage to red cell membranes and result in myelin and axonal damage.
In a girl with CD59 deficiency (HACD59; 612300), progressive neurologic dysfunction, and hemolytic anemia, Hochsmann et al. (2014) identified a homozygous 1-bp deletion (c.146delA) in exon 5 of the CD59 gene, resulting in a frameshift and premature termination (Asp49ValfsTer31). Her unaffected parents were heterozygous for the mutation. The patient first presented at age 7 months with generalized hypotonia, bulbar symptoms, and areflexia. During later febrile episodes, she developed hemolytic anemia with progressive neurologic deterioration, including T2-weighted hyperintense lesions on brain MRI, seizures, and visual impairment. Flow cytometric analysis of patient peripheral blood cells showed isolated CD59 deficiency. Treatment with eculizumab, an inhibitor of the complement membrane-attack complex, resulted in neurologic improvement about 6 months later. At age 5.5 years, the patient could eat and swallow normally, could walk short distances with support, and had improved cognitive and speech production.
Acosta, J., Hettinga, J., Fluckiger, R., Krumrei, N., Goldfine, A., Angarita, L., Halperin, J. Molecular basis for a link between complement and the vascular complications of diabetes. Proc. Nat. Acad. Sci. 97: 5450-5455, 2000. [PubMed: 10805801] [Full Text: https://doi.org/10.1073/pnas.97.10.5450]
Bickmore, W. A., Longbottom, D., Oghene, K., Fletcher, J. M., van Heyningen, V. Colocalization of the human CD59 gene to 11p13 with the MIC11 cell surface antigen. Genomics 17: 129-135, 1993. [PubMed: 7691713] [Full Text: https://doi.org/10.1006/geno.1993.1293]
Davies, A., Simmons, D. L., Hale, G., Harrison, R. A., Tighe, H., Lachmann, P. J., Waldmann, H. CD59, an LY-6-like protein expressed in human lymphoid cells, regulates the action of the complement membrane attack complex on homologous cells. J. Exp. Med. 170: 637-654, 1989. [PubMed: 2475570] [Full Text: https://doi.org/10.1084/jem.170.3.637]
Forsberg, U. H., Bazil, V., Stefanova, I., Schroder, J. Gene for human CD59 (likely Ly-6 homologue) is located on the short arm of chromosome 11. Immunogenetics 30: 188-193, 1989. [PubMed: 2476389] [Full Text: https://doi.org/10.1007/BF02421205]
Gawin, B., Niederfuhr, A., Schumacher, N., Hummerich, H., Little, P. F. R., Gessler, M. A 7.5 Mb sequence-ready PAC contig and gene expression map of human chromosome 11p13-p14.1. Genome Res. 9: 1074-1086, 1999. [PubMed: 10568747] [Full Text: https://doi.org/10.1101/gr.9.11.1074]
Harada, R., Okada, N., Fujita, T., Okada, H. Purification of 1F5 antigen that prevents complement attack on homologous cell membranes. J. Immun. 144: 1823-1828, 1990. [PubMed: 2307842]
Heckl-Ostreicher, B., Ragg, S., Drechsler, M., Scherthan, H., Royer-Pokora, B. Localization of the human CD59 gene by fluorescence in situ hybridization and pulsed-field gel electrophoresis. Cytogenet. Cell Genet. 63: 144-146, 1993. [PubMed: 7683594] [Full Text: https://doi.org/10.1159/000133522]
Hochsmann, B., Dohna-Schwake, C., Kyrieleis, H. A., Pannicke, U., Schrezenmeier, H. Targeted therapy with eculizumab for inherited CD59 deficiency. (Letter) New Eng. J. Med. 370: 90-92, 2014. [PubMed: 24382084] [Full Text: https://doi.org/10.1056/NEJMc1308104]
Holt, D. S., Botto, M., Bygrave, A. E., Hanna, S. M., Walport, M. J., Morgan, B. P. Targeted deletion of the CD59 gene causes spontaneous intravascular hemolysis and hemoglobinuria. Blood 98: 442-449, 2001. [PubMed: 11435315] [Full Text: https://doi.org/10.1182/blood.v98.2.442]
Holt, D. S., Powell, M. B., Rushmere, N. K., Morgan, B. P. Genomic structure and chromosome location of the gene encoding mouse CD59. Cytogenet. Cell Genet. 89: 264-267, 2000. [PubMed: 10965140] [Full Text: https://doi.org/10.1159/000015630]
Huppi, K., Duncan, R., Potter, M. Myc-1 is centromeric to the linkage group Ly-6-Sis-Gdc-1 on mouse chromosome 15. Immunogenetics 27: 215-219, 1988. [PubMed: 2892786] [Full Text: https://doi.org/10.1007/BF00346589]
Kamiura, S., Nolan, C. M., Meruelo, D. Long-range physical map of the Ly-6 complex: mapping the Ly-6 multigene family by field-inversion and two-dimensional gel electrophoresis. Genomics 12: 89-105, 1992. [PubMed: 1733867] [Full Text: https://doi.org/10.1016/0888-7543(92)90411-k]
Kumar, A., Godwin, J. W., Gates, P. B., Garza-Garcia, A. A., Brockes, J. P. Molecular basis for the nerve dependence of limb regeneration in an adult vertebrate. Science 318: 772-777, 2007. [PubMed: 17975060] [Full Text: https://doi.org/10.1126/science.1147710]
LeClair, K. P., Rabin, M., Nesbitt, M. N., Pravtcheva, D., Ruddle, F. H., Palfree, R. G. E., Bothwell, A. Murine Ly-6 multigene family is located on chromosome 15. Proc. Nat. Acad. Sci. 84: 1638-1642, 1987. [PubMed: 2882510] [Full Text: https://doi.org/10.1073/pnas.84.6.1638]
Mao, M., Yu, M., Tong, J.-H., Ye, J., Zhu, J., Huang, Q.-H., Fu, G., Yu, L., Zhao, S.-Y., Waxman, S., Lanotte, M., Wang, Z.-Y., Tan, J.-Z., Chan, S.-J., Chen, Z. RIG-E, a human homolog of the murine Ly-6 family, is induced by retinoic acid during the differentiation of acute promyelocytic leukemia cell. Proc. Nat. Acad. Sci. 93: 5910-5914, 1996. [PubMed: 8650192] [Full Text: https://doi.org/10.1073/pnas.93.12.5910]
Meri, S., Morgan, B. P., Davies, A., Daniels, R. H., Olavesen, M. G., Waldmann, H., Lachmann, P. J. Human protectin (CD59), an 18,000-20,000 MW complement lysis restricting factor, inhibits C5b-8 catalysed insertion of C9 into lipid bilayers. Immunology 71: 1-9, 1990. [PubMed: 1698710]
Meri, S., Morgan, B. P., Wing, M., Jones, J., Davies, A., Podack, E., Lachmann, P. J. Human protectin (CD59), an 18-20-kD homologous complement restriction factor, does not restrict perforin-mediated lysis. J. Exp. Med. 172: 367-370, 1990. [PubMed: 1694224] [Full Text: https://doi.org/10.1084/jem.172.1.367]
Morais da Silva, S., Gates, P. B., Brockes, J. P. The newt ortholog of CD59 is implicated in proximodistal identity during amphibian limb regeneration. Dev. Cell 3: 547-555, 2002. [PubMed: 12408806] [Full Text: https://doi.org/10.1016/s1534-5807(02)00288-5]
Motoyama, N., Okada, N., Yamashina, M., Okada, H. Paroxysmal nocturnal hemoglobinuria due to hereditary nucleotide deletion in the HRF20 (CD59) gene. Europ. J. Immun. 22: 2669-2673, 1992. [PubMed: 1382994] [Full Text: https://doi.org/10.1002/eji.1830221029]
Nevo, Y., Ben-Zeev, B., Tabib, A., Straussberg, R., Anikster, Y., Shorer, Z., Fattal-Valevski, A., Ta-Shma, A., Aharoni, S., Rabie, M., Zenvirt, S., Goldshmidt, H., Fellig, Y., Shaag, A., Mevorach, D., Elpeleg, O. CD59 deficiency is associated with chronic hemolysis and childhood relapsing immune-mediated polyneuropathy. Blood 121: 129-135, 2013. [PubMed: 23149847] [Full Text: https://doi.org/10.1182/blood-2012-07-441857]
Okada, N., Harada, R., Fujiita, T., Okada, H. A novel membrane glycoprotein capable of inhibiting membrane attack by homologous complement. Int. Immun. 1: 205-208, 1989. [PubMed: 2487685] [Full Text: https://doi.org/10.1093/intimm/1.2.205]
Petranka, J. G., Fleenor, D. E., Sykes, K., Kaufman, R. E., Rosse, W. F. Structure of the CD59-encoding gene: further evidence of a relationship to murine lymphocyte antigen Ly-6 protein. Proc. Nat. Acad. Sci. 89: 7876-7879, 1992. Note: Erratum: Proc. Nat. Acad. Sci. 90: 5878 only, 1993. [PubMed: 1381503] [Full Text: https://doi.org/10.1073/pnas.89.17.7876]
Rother, R. P., Rollins, S. A., Mennone, J., Chodera, A., Fidel, S. A., Bessler, M., Hillmen, P., Squinto, S. P. Expression of recombinant transmembrane CD59 in paroxysmal nocturnal hemoglobinuria B cells confers resistance to human complement. Blood 84: 2604-2611, 1994. [PubMed: 7522635]
Sood, R., Zehnder, J. L., Druzin, M. L., Brown, P. O. Gene expression patterns in human placenta. Proc. Nat. Acad. Sci. 103: 5478-5483, 2006. [PubMed: 16567644] [Full Text: https://doi.org/10.1073/pnas.0508035103]
Tone, M., Walsh, L. A., Waldmann, H. Gene structure of human CD59 and demonstration that discrete mRNAs are generated by alternative polyadenylation. J. Molec. Biol. 227: 971-976, 1992. [PubMed: 1383553] [Full Text: https://doi.org/10.1016/0022-2836(92)90239-g]
Walsh, L. A., Tone, M., Thiru, S., Waldmann, H. The CD59 antigen--a multifunctional molecule. Tissue Antigens 40: 213-220, 1992. [PubMed: 1282740] [Full Text: https://doi.org/10.1111/j.1399-0039.1992.tb02048.x]
Woodroofe, M. N., Tunnacliffe, A., Pym, B., Goodfellow, P. N., Walsh, F. S. Human muscle cell surface antigen 16-3A5 is encoded by a gene on chromosome 11. Somat. Cell Molec. Genet. 10: 535-540, 1984. [PubMed: 6382636] [Full Text: https://doi.org/10.1007/BF01534858]